Contribution of the peripheral 5-HT 2A receptor to mechanical hyperalgesia in a rat model of neuropathic pain

Neurochem Int. 2005 Nov;47(6):394-400. doi: 10.1016/j.neuint.2005.06.002.


We investigated the effect of 5-HT receptor antagonists on mechanical hyperalgesia observed in a neuropathic pain rat model prepared by chronic constriction injury of the sciatic nerve. NAN-190, a 5-HT 1A receptor antagonist, (-)-pindolol, a 5-HT 1A/1B receptor antagonist, and tropisetron, a 5-HT(3/4) receptor antagonist, did not affect the pain threshold in the hyperalgesic hind limb to the same extent as in the normal hind limb. However, sarpogrelate and ketanserin, 5-HT 2A receptor antagonists, significantly elevated the pain threshold in the hyperalgesic hind limb, but not in the normal hind limb. In spite of its high affinity for the 5-HT 2A receptor, methysergide only slightly elevated the pain threshold in the hyperalgesic hind limb. Pre-treatment with methysergide significantly antagonized the inhibitory effect of sarpogrelate on hyperalgesia. Furthermore, the 5-HT 2A receptor specific binding activity of 3H-ketanserin determined for the hyperalgesic hind limb did not differ from that of the normal hind limb. From these results, we propose that the 5-HT 2A receptor in the hyperalgesic hind paw function as an agonist-independent active receptor following constriction of the sciatic nerve, and that sarpogrelate and ketanserin act as inverse agonists of this receptor and suppress its activation. Methysergide may act as a neutral antagonist that blocks the effect of inverse agonists on the 5-HT 2A receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Binding, Competitive / drug effects
  • Binding, Competitive / physiology
  • Denervation
  • Disease Models, Animal
  • Drug Interactions / physiology
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism*
  • Hyperalgesia / physiopathology
  • Ketanserin / pharmacology
  • Ligation
  • Male
  • Neuralgia / drug therapy
  • Neuralgia / metabolism*
  • Neuralgia / physiopathology
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Peripheral Nerves / drug effects
  • Peripheral Nerves / metabolism
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / metabolism*
  • Peripheral Nervous System Diseases / physiopathology
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Sciatic Neuropathy / metabolism*
  • Sciatic Neuropathy / physiopathology
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • Succinates / pharmacology


  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Succinates
  • sarpogrelate
  • Ketanserin